Autoimmune regulator induced changes in the gene expression profile of human monocyte-dendritic cell-lineage

Abstract

The autoimmune regulator (AIRE) is a transcriptional regulator expressed in the thymic medullary epithelial cells and in the cells of the monocyte-dendritic lineage both in the thymus and in the secondary lymphoid organs. Mutations in the AIRE gene cause autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), a recessively inherited disease characterized by loss of immunological self-tolerance to multiple endocrine organs. Recent mouse knockout studies suggest that AIRE is responsible for ectopic expression of peripheral self-antigens in the thymus. In the present study, we detected an increased level of endogenous AIRE expression during the differentiation process of the human monocyte derived dendritic cells (MoDCs). We subsequently identified candidates for AIRE-regulated genes by using cDNA microarray technology to analyse the changes in the gene expression profile brought about by overexpressing the AIRE protein in the monocytic U937 cells. The changes observed resembled those previously reported to occur during the maturation of DCs, including up-regulation of the CCL22, CD25, ICAM-1 and RelB genes. In contrast, increased expression of the steroidogenic enzymes P450c17, P450c21 and P450scc, the major autoantigens in APECED, was not found either in our cell model or in the dendritic cell cultures. We also identified the ERK signal transduction pathway as a candidate for mediating the signal that results in the altered expression profile. Our findings suggest that the role of AIRE in the DCs differs from its function in the thymus.